CN1209353C - Estrogen agonist/antagonist metabolites - Google Patents

Estrogen agonist/antagonist metabolites Download PDF

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CN1209353C
CN1209353C CNB018077935A CN01807793A CN1209353C CN 1209353 C CN1209353 C CN 1209353C CN B018077935 A CNB018077935 A CN B018077935A CN 01807793 A CN01807793 A CN 01807793A CN 1209353 C CN1209353 C CN 1209353C
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compound
metabolite
gram
pptn
cancer
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CN1422263A (en
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韦斯利·W·戴
金·A·约翰逊
钱德拉·A·帕拉卡什
詹姆斯·F·埃格勒
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Pfizer Products Inc
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Abstract

This invention relates to compounds that are mammalian metabolites of (-)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydronaphthalene-2-ol. The compounds of the invention can be used as standards for analytical assays or as intermediates for the further chemical synthesis or biosynthesis of chemical entities. The invention also relates to pharmaceutical compositions for the treatment of disease and methods of treating disease.

Description

Estrogen agonist/antagonist metabolites
Invention field
The present invention relates to (-)-suitable-6-phenyl-5-[4-(2-tetramethyleneimine-1-base-oxyethyl group)-phenyl as the Mammals metabolite]-5,6,7, the compound of 8-naphthane-2-alcohol.Compound of the present invention is used as standard and is used as therapeutical agent in analytical test.
Background of invention
On pharmacology, (-)-suitable-6-phenyl-5-[4-(2-tetramethyleneimine-1-base-oxyethyl group)-phenyl]-5,6,7,8-tetrahydrochysene-naphthalene-2-alcohol (PPTN) is a kind of estrogen agonist/antagonist, it is at United States Patent (USP) 5,552, is disclosed in 412." estrogen agonist/antagonist " is the compound that influences the identical acceptor of some rather than all estrogen effect, and its can antagonism or retardance oestrogenic hormon in some cases.It is also referred to as " estrogenic agents selectively " (SERM).Estrogen agonist/antagonist also can be called as the estrogen antagonist agent, although they have some estrogenic activity in some estrogen receptor.Therefore estrogen agonist/antagonist is not commonly referred to as " pure estrogen antagonist agent ".Can also be called as the agent of I type estrogen antagonist as the estrogen antagonist agent of agonist.The agent of I type estrogen antagonist activates estrogen receptor and is combined in tightly for a long time in the nuclear, additional impaired acceptor (Clark waits the people, Steroids1973; 22:707; People such as Capony, Mol Cell Endocrinol, 1975; 3:233).
Compound of the present invention is the metabolite of PPTN and is considered to have significant pharmacological activity, with parent compound PPTN had active similar or identical.
The accompanying drawing summary
Fig. 1 is the representational HPLC radiochromatogram of the urine metabolite of PPTN in the mouse after oral.The scale of the longitudinal axis is the radioactivity with count per minute (CPM) expression.The scale of transverse axis is with minute residence time of expression.。
Fig. 2 is the representational HPLC radiochromatogram of the movement metabolite of PPTN in the mouse after oral.The scale of the longitudinal axis is the radioactivity with count per minute (CPM) expression.The scale of transverse axis is with minute residence time of expression.
Fig. 3 is the representational HPLC radiochromatogram of the cyclic metabolism thing of PPTN in the mouse after oral.The scale of the longitudinal axis is the radioactivity with count per minute (CPM) expression.The scale of transverse axis is with minute residence time of expression.
Fig. 4 is cracking process figure and the mass-spectrometric data of PPTN metabolite XI.The scale of the longitudinal axis is a relative abundance.The scale of transverse axis is a mass-to-charge ratio; M/z.
Fig. 5 is cracking process figure and the mass-spectrometric data of PPTN metabolite XII.The scale of the longitudinal axis is a relative abundance.The scale of transverse axis is a mass-to-charge ratio; M/z.
Fig. 6 is cracking process figure and the mass-spectrometric data of PPTN metabolite XXI.The scale of the longitudinal axis is a relative abundance.The scale of transverse axis is a mass-to-charge ratio; M/z.
Fig. 7 is cracking process figure and the mass-spectrometric data of PPTN metabolite XIV.The scale of the longitudinal axis is a relative abundance.The scale of transverse axis is a mass-to-charge ratio; M/z.
Fig. 8 is cracking process figure and the mass-spectrometric data of PPTN metabolite VI.The scale of the longitudinal axis is a relative abundance.The scale of transverse axis is a mass-to-charge ratio; M/z.
Fig. 9 is cracking process figure and the mass-spectrometric data of PPTN metabolite II.The scale of the longitudinal axis is a relative abundance.The scale of transverse axis is a mass-to-charge ratio; M/z.
Figure 10 is cracking process figure and the mass-spectrometric data of PPTN metabolite XVI.The scale of the longitudinal axis is a relative abundance.The scale of transverse axis is a mass-to-charge ratio; M/z.
Figure 11 is cracking process figure and the mass-spectrometric data of PPTN metabolite X.The scale of the longitudinal axis is a relative abundance.The scale of transverse axis is a mass-to-charge ratio; M/z.
Figure 12 is cracking process figure and the mass-spectrometric data of PPTN metabolite XVII.The scale of the longitudinal axis is a relative abundance.The scale of transverse axis is a mass-to-charge ratio; M/z.
Figure 13 is cracking process figure and the mass-spectrometric data of PPTN metabolite IV.The scale of the longitudinal axis is a relative abundance.The scale of transverse axis is a mass-to-charge ratio; M/z.
Figure 14 is cracking process figure and the mass-spectrometric data of PPTN metabolite XV.The scale of the longitudinal axis is a relative abundance.The scale of transverse axis is a mass-to-charge ratio; M/z.
Figure 15 is cracking process figure and the mass-spectrometric data of PPTN metabolite V.The scale of the longitudinal axis is a relative abundance.The scale of transverse axis is a mass-to-charge ratio; M/z.
Figure 16 is cracking process figure and the mass-spectrometric data of PPTN metabolite XIII.The scale of the longitudinal axis is a relative abundance.The scale of transverse axis is a mass-to-charge ratio; M/z.
Figure 17 is cracking process figure and the mass-spectrometric data of PPTN metabolite IX.The scale of the longitudinal axis is a relative abundance.The scale of transverse axis is a mass-to-charge ratio; M/z.
Figure 18 is cracking process figure and the mass-spectrometric data of PPTN metabolite VIII.The scale of the longitudinal axis is a relative abundance.The scale of transverse axis is a mass-to-charge ratio; M/z.
Summary of the invention
The present invention relates to as the Mammals estrogen agonist/antagonist metabolite of PPTN.
Second aspect of the present invention relates to metabolite or its optically-active or the geometrical isomer that comprises PPTN, or its pharmacy acceptable salt, N-oxide compound, ester, quaternary ammonium salt, and the pharmaceutical composition of pharmaceutically acceptable carrier, vehicle or thinner.
The 3rd aspect of the present invention relates to the method for the treatment of disease, comprises the PPTN metabolite with pharmacological activity or its pharmacy acceptable salt, N-oxide compound, ester or the quaternary ammonium salt of effective dosage.The metabolite of PPTN is effectively, reduces the susceptibility that the side effect relevant with the oestrogenic hormon administration followed simultaneously basically.
The 4th aspect of the present invention provides the human consumer to use the medicine box of treatment disease.This medicine box comprises a) metabolite of mammiferous PPTN; And optional b) specification sheets that uses PPTN metabolite treatment disease method is described.Specification sheets can indicate that also this medicine box is to be used for treatment of diseases, reduces the susceptibility that the side effect relevant with the oestrogenic hormon administration followed simultaneously basically.
The 5th aspect of the present invention relates to the medicine box that is used as analytical standard in measuring PPTN metabolite or its pharmacy acceptable salt, N-oxide compound, ester and quaternary ammonium salt.This medicine box comprises the PPTN metabolite and the container that is used to accommodate metabolite of pure form basically.
The purposes that the 6th aspect of the present invention provides mammiferous PPTN metabolite or its pharmacy acceptable salt, N-oxide compound, ester and quaternary ammonium salt to be used to produce medicine.
Detailed Description Of The Invention
The present invention relates to the metabolite of PPTN.This metabolite is corresponding to the compound by formula 1 expression:
Figure C0180779300121
R wherein 1Be selected from
Figure C0180779300131
Or-NH (CH 2) 3COR 6
R 5Be selected from H, CH 3, glucuronic acid and SO 3H;
R 2, R 3, R 4And R 7Identical or different, be selected from H and OR 5And
R 6Be selected from-OH ,-NHCH 2COOH, glucuronic acid and-NHCH 2CH 2SO 3H,
Condition is:
(a) if R 1Be
Figure C0180779300132
Or-NH (CH 2) 3COOH and
(b) R 2Be OH or OCH 3, R 3And R 7Be H, if perhaps R 1Such as in above-mentioned (a) definition, and
(c) R 2And R 7Be H, and R 3Be OH or OCH 3,
R so 4Not H.
Preferred formula (I) compound comprises such compound: R wherein 1Be selected from
Figure C0180779300133
Or-NH (CH 2) 3COR 6
R 5Be selected from H or CH 3R 2, R 3, R 4And R 7Identical or different, be selected from H and OR 5And
R 6Be selected from-OH or-NHCH 2COOH,
Condition is:
(a) if R 1Be
Figure C0180779300141
Or-NH (CH 2) 3COOH and
(b) R 2Be OH or OCH 3, and R 3And R 7Be H, if perhaps R 1Such as in above-mentioned (a) definition, and
(c) R 2And R 7Be H, and R 3Be OH or OCH 3,
R so 4Not H.
Preferred PPTN metabolite compound comprises those compounds that exemplify in the Table I.
Table I: preferred PPTN metabolite:
Figure C0180779300151
Figure C0180779300161
Figure C0180779300181
Figure C0180779300191
Preferred PPTN metabolite compound comprises those that exemplify in the Table II.
Table II: preferred PPTN metabolite:
Figure C0180779300201
Figure C0180779300211
On the other hand, the present invention relates to pure basically aforesaid PPTN metabolite.Except as otherwise noted, following definition is suitable for:
" treatment " used herein comprises (for example preventative) of prevention and the treatment of alleviating, and " treatment " used herein refers to the effect that prevention and/or remissive treatment are provided.
" patient " is meant and can comprises the mankind with the animal of The compounds of this invention, composition, method and medicine box treatment.Term " patient " is meant masculinity and femininity, unless indicate sex particularly.Preferred patient is postclimacteric woman.
" side effect relevant with oestrogenic hormon " comprises breast tenderness, mammary cancer, swells, headache, coagulation of blood increases and women's menstruation is bled.Unopposed estrin treatment has increased the danger of carcinoma of endometrium.The perhaps existing danger that increases of the women of long term oestrogen therapy, its can not by and the progestogen deposited reverse (N.Enal.J.Med.1995; 332:1589).In the male sex, estrogenic side effect comprises blood coagulation increase, gynecomastia, womanlike and sexual desire reduction.
Term " postclimacteric women " definition not only comprises the old women that has passed through climacteric, and comprise and hysterectomizing or that for example those carry out the long term administration reflunomide, suffer from the women of Cushing's syndrome or gonadal agenesis owing to other some reasons suppress the women that oestrogenic hormon generate.
" mammary cancer " is defined as chest conduit or the epithelial neoplasm of leaflet internal layer.
" glucuronic acid " is to transfer in the metabolite or transfer to the substituting group that is formed metabolite in the parent compound by the phase II conjugation reaction of glucoside acidifying.Acid on glucuronic acid and metabolite or the parent compound or alcohol or phenolic groups reaction form " glucuronide ".The glucuronide substituting group is abbreviated as " Glu " or " glucuronide " here in the formula.
" sulfuric acid " is to transfer in the metabolite or transfer to the substituting group that is formed metabolite in the parent compound by Sulfated phase II conjugation reaction.Alcohol on sulfuric acid and metabolite or the parent compound or phenolic groups reaction form " sulfuric ester ".
" co-administered " of PPTN metabolite and the combination of other compounds is meant that these components can be used as composition or as part administration together identical, single formulation." co-administered " also comprise administration PPTN metabolite respectively and other compound but as the part of identical treatment scheme or system.This component does not need basically administration simultaneously, although if need them can co-administered yet.Therefore " co-administered " for example comprise as the dosage that separates or formulation, but administration PPTN metabolite and other compound simultaneously." co-administered " also is included in the different time and with any order separate administration.For example, as the component that suitable patient can use one or more treatments in the morning, use one or more another kind of components at night.
The chemist of ordinary skill will recognize that compounds more of the present invention will contain one or more atoms, and it can be specific stereochemistry, tautomerism or geometric configuration, produce steric isomer, tautomer, zone and configuration isomer.All these isomer and composition thereof include in the present invention.The hydrate and the solvate that also comprise The compounds of this invention.
The present invention also comprises isotope-labeled compound, it is structurally identical with shown in other compound Chinese styles I-XXV that the present invention includes those, but in fact one or more atoms are different from the atomic mass in fact measured usually by atomic mass or total mass number or the atom of total mass number substitutes.Can add isotopic example in the The compounds of this invention comprises and for example is respectively the isotropic substance of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine and chlorine 2H, 3H, 13C, 14C, 15N, 18O, 17O, 31P, 32P, 35S, 18F and 36Cl.Contain above-mentioned isotropic substance and/or other atoms other isotopic The compounds of this invention, its prodrug and described compound or described prodrug pharmacy acceptable salt all within the scope of the present invention.Isotope-labeled compounds more of the present invention for example for example wherein mix radioactive isotropic substance 3H and 14Those of C are used for medicine and/or matrix organization's distribution test.Tritium promptly 3H and carbon-14 are promptly 14The C isotropic substance is because easily preparation and detect and preferred especially.In addition, for example heavy hydrogen is promptly with heavy isotope 2H replaces, can obtain by bigger metabolic stability for example in the body transformation period increase or the dosage that needs reduces and produces specific treatment advantage, so perhaps it be preferred in some cases.In general the compound of isotope-labeled formula I-XXV of the present invention and prodrug thereof can prepare by method or those methods known in the art of carrying out exemplifying below. 14C-PPTN can be by the method for summarizing and exemplifying in the United States Patent (USP) 5,552,412, by replacing not having isotope-labeled reactant to prepare with the isotope-labeled reactant that obtains easily.
With the PPTN metabolite of the form of mixtures of pure basically form or known component, can be as being used for chemosynthesis or the new chemical entity of biosynthesizing in analytical standard external or metabolic studies in vivo or as intermediate.Metabolite can be with solid or separated in solution.
Compound of the present invention is considered to can be used for treatment of diseases.Example for effective disease of compound or state comprises osteoporosis, mammary cancer, hyperlipidaemia, atherosclerosis, Alzheimer, cataract, the sexual desire loss, man's sexual dysfunction, colorectal carcinoma, wrinkle of skin, autoimmune disease, alopecia, acne, cardiovascular diseases, cataract, diabetes, endometriosis, woman's sexual dysfunction, hyperglycemia, fat, obsessive-compulsive disorder, premenstrual tension syndrome, prostate cancer, benign prostatomegaly, pulmonary hypertension, reperfusion injury, rheumatoid arthritis, osteoarthritis, seborrheic dermatitis, old gynecomastia, testosterone lacks and to the testosterone responsive illness that rises, Turner's syndrome, the fibrosis in uterus, atrophic vaginitis, incontinence, uterus carcinoma, hirsutism, Bulimia nerovsa, apocleisis, hypoactive sexual desire, the property illness of swash waking up, dyspareunia, vagismus and promotion wound healing.This compound is increasing the orgasm frequency, the treatment prolapsus, reduce the pH of vagina, the treatment urinary tract infections, the arterial occlusive disease of treatment or preventing apoplectic, myocardial infarction, acute or chronic renal failure, periphery and Raynaud's phenomenon and treatment ovary, liver and carcinoma of the pancreas and stiff fibre cancer, neurospongioma and kidney cell cancer aspect also are effective.The method that is used for the treatment of one or more above-mentioned diseases or symptom comprises the PPTN metabolite of effective dosage.
In methods of treatment of the present invention, metabolite can directly be administered into the patient, and for example in table, perhaps metabolite can generate in patient body by metabolism and come administration.For example, metabolite of the present invention can be effectively to patient's administration with treatment disease or illness, by to a certain amount of PPTN of patient's administration, after administration, desirable metabolite forms in patient body by metabolism.In addition, the medicine-feeding way of PPTN and dosage can be according to requiring change, to obtain the productive rate of desirable bulk concentration and metabolite.
When being used for the treatment of one or more above-mentioned diseases, the PPTN metabolite can be used in combination (perhaps co-administered or in identical pharmaceutical composition) respectively with statins, and statins for example is disclosed in U.S.4, the simvastatin in 444,784; Be disclosed in U.S.4, the pravastatin in 346,227; Be disclosed in U.S.5, the cerivastatin in 502,199; Be disclosed in U.S.3, the mevastatin in 983,140; Be disclosed in U.S.4, the velostatin in 448,784 and U.S.4,450,171; Be disclosed in U.S.4, the fluvastatin in 739,073; Be disclosed in U.S.4, the compactin in 804,770; Be disclosed in U.S.4, the lovastatin in 231,938; Be disclosed in european patent application and disclose dalvastatin among 738510 A2; Be disclosed in european patent application and disclose fluindostatin among 363934 A1; Be disclosed in United States Patent (USP) 4,681, the atorvastatin in 893; Be disclosed in United States Patent (USP) 5,273, the atorvastatin calcium in 995; Be disclosed in U.S.4, the dihydrocompactin in 450,171; Be disclosed in United States Patent (USP) 5,260, the ZD-4522 in 440; Be disclosed in United States Patent (USP) 5,082, the bervastatin in 859; And be disclosed in United States Patent (USP) 5,102, the NK-104 in 888.The PPTN metabolite can also with for example alendronic acid of bisphosphonates compound, alendronate, cimadronate, clodronic acid, clodronate, 1-hydroxyl-3-(1-pyrrolidyl)-propylidene-1,1-di 2 ethylhexyl phosphonic acid, etidronic acid, ibandronate, neridronate, olpadronate, pamidronate, piridronate, risedronate, tiludronate and zolendronate are used in combination.In addition; the PPTN metabolite can with cyclic guanosine 3 '; 5 '-single phosphoric acid elevator for example sildenafil (1-[[3-(6; 7-dihydro-1-methyl-7-oxo-3-propyl group-1H-pyrazoles [4,3-d] pyrimidine-5-yl)-and 4-oxyethyl group-phenyl] alkylsulfonyl]-4-methylpiperazine Citrate trianion) be used in combination.
The pharmaceutically-acceptable acid addition of The compounds of this invention can be formed by compound itself, or is formed by its any ester, and comprises the pharmacy acceptable salt that usually is used for pharmaceutical chemistry.For example, can form salt with inorganic and organic acid, described acid is hydrochloric acid for example, Hydrogen bromide, hydroiodic acid HI, sulfonic acid, comprise the reagent that naphthene sulfonic acid, methylsulfonic acid and toluenesulphonic acids are such, sulfuric acid, nitric acid, phosphoric acid, tartrate, pyrosulfuric acid, metaphosphoric acid, succsinic acid, formic acid, phthalic acid and lactic acid etc., most preferred is to form salt with hydrochloric acid, citric acid, phenylformic acid, toxilic acid, acetate and propionic acid.
As discussed above, compound of the present invention can be with the pharmacy acceptable salt form administration.This salt can be as common in the organic chemistry forms easily, by with basic cpd of the present invention and for example suitable as mentioned above acid-respons.This salt forms with high yield under suitable temperature soon, usually only prepares by separating compound from the suitable acidic cleaning of the synthetic final step of conduct.The salifiable acid of shape is dissolved in appropriate organic solvent, or aqueous organic solvent for example alkanol, ketone or ester.On the other hand, if the compound of invention is wished the form with free alkali, it is separated from the final washing methods of alkalescence according to common operation.The technology that preferably is used for preparing hydrochloride is that free alkali is dissolved in appropriate solvent, is for example using molecular sieve finish-drying solution before wherein bubbling is gone into hydrogen chloride gas.
When as medicine, The compounds of this invention changes quite greatly to the dosage of people's administration, by attending doctor's judgement.What should be noted that is, when for example during the lauroleate form administration, needing to regulate the dosage of compound with salt, wherein salify partly has estimable molecular weight.The general range of the effective dosage of this compound is about 0.001mg/ days-approximately 200mg/ days.Preferred range is about 0.01mg/ days-100mg/ days.Certainly, in fact usually at the compound of different time gradation administration dosage every day every day.Yet under any given situation, the amount of the compound of administration will depend on such factor for example solubleness, the preparation and the administration path of use of active ingredient.
The administration path of The compounds of this invention is not conclusive.This compound can absorb from digestive tube, yet if in given situation, need this compound also can percutaneous dosing, or absorb by rectum as suppository.The composition of all common types be can use, tablet, masticable tablet, capsule, solution, parenteral solution, lozenge, suppository and suspension comprised.Composition be mixed with comprise every day dosage or suitably part every day dosage unitary dose, it can be the liquid of single tablet or capsule or appropriate amount.
Generally speaking, all compositions according to usual method preparation in the pharmaceutical chemistry and/or in body or external metabolic reaction for example here exemplified those separate.Parent compound PPTN those method preparations by summarizing in the United States Patent (USP) 5,552,412 and/or exemplifying.It is synthetic that metabolite can directly synthesize maybe those that can for example describe among the embodiment by external or body endoenzyme or metabolic reaction.
The method of preparation is known in the art and is disclosed in for example Remington:The Scienceand Practice of Pharmacy, Mack Publishing Company, and Easton is in the Pa.19th version (1995).Be used for pharmaceutical composition within the present invention and can be the capsule, suppository, lyophilized powder of the liquor of aseptic, non-heating or suspension, dressing, through patch or other form known in the art of skin.
Capsule prepares by compound is mixed with the suitable dilution agent then an amount of mixture to be filled in the capsule.Common thinner comprises for example many different types of starch of inertia powdered material, powdered Mierocrystalline cellulose particularly Mierocrystalline cellulose, sugar for example fructose, mannitol and sucrose, grain flour and the similar edible powder of crystalline and crystallite.
Tablet is by directly compressing, preparing by wet granulation or by dry granulation.The common mixed diluent of their preparation, binding agent, lubricant and disintegrating agent and described compound.Common thinner comprises for example dissimilar starch, lactose, mannitol, kaolin, calcium phosphate or calcium sulfate, inorganic salt for example sodium-chlor and powdered sugar.The powdered derivatived cellulose also is useful.General tablet binding agent is for example for example lactose, fructose, a glucose etc. of starch, gelatin and sugar of such material.Natural and synthetic natural gum also is easily, comprises gum arabic, alginate, methylcellulose gum, polyvinylpyrrolidine etc.Polyoxyethylene glycol, ethyl cellulose and wax also can be used as binding agent.
Perhaps, lubricant is essential adhering in mould with prevention tablet and drift in tablet formulation.Lubricant is selected from so slick solid for example stearate, stearic acid and the hydrogenant vegetables oil of talcum, magnesium and calcium.
Tablet disintegrant is to promote disintegration of tablet to discharge the material of compound when tablet becomes wet.They comprise starch, clay, Mierocrystalline cellulose, phycocolloid and natural gum, more especially corn and yam starch, methylcellulose gum, agar, bentonite, lignocellulose, powdered natural sponge, Zeo-karb, alginic acid, guar gum, lemon pulp and carboxymethyl cellulose for example also can use Sodium Lauryl Sulphate BP/USP.
Tablet usually scribbles sugar as seasonings and sealing agent, or scribbles the film forming protective material to improve the dissolution characteristics of tablet.This compound also can be by in preparation, using a large amount of pleasant flavor material for example mannitol, the method now determined very much according to this area are mixed with chewable tablet.
When hope is given drug compound as suppository, can use general alkali.Theobroma oil is traditional suppository alkali, and it can improve to improve its fusing point slightly by adding wax.Can comprise that particularly different molecular weight polyethylene glycol can be used widely with the miscible suppository alkali of water.
The effect of The compounds of this invention can postpone or prolongation by suitable preparation.For example, can preparing slowly, the particle of soluble compound is mixed in tablet or the capsule then.This technology can be improved with particulate mixture filled capsules then by the particle that makes several different dissolution rate.Tablet or capsule can scribble and stop the dissolved film in for some time that can estimate.Even parenteral preparation can be by with compound dissolution or be suspended in and it only be dispersed in oil in the slurries or the emulsive vehicle at leisure make long lasting preparation.
Term " prodrug " meaning refers to be transformed in vivo the compound that forms The compounds of this invention.This conversion can for example take place by hydrolysis in blood by different mechanism.Utilize the good discussion of prodrug to be provided at T.Higuchi and W.Stella, " Pro-dr μ gs as Novel Delivery Systems, " Vol.14of the A.C.S.Symposium Series, and Bioreversible Carriers in Drug Design, ed.Edward B.Roche, American Pharmaceutical Association and Pergamon Press is in 1987.
For example, if compound of the present invention comprises carboxylic acid functional, prodrug can comprise the ester that replaces the hydrogen atom of acidic group to form by with following group: (C for example 1-C 8) alkyl, (C 2-C 12) chain alkyloyloxyethyl methyl, 1-(chain alkyloyloxyethyl) ethyl that contains 4-9 carbon atom, 1-methyl isophthalic acid-(chain alkyloyloxyethyl) ethyl that contains 5-10 carbon atom, the alkoxy carbonyl yloxy ylmethyl that contains 3-6 carbon atom, the 1-(alkoxyl group carbonyl oxygen base) that contains 4-7 carbon atom, 1-methyl isophthalic acid-(alkoxycarbonyloxy) ethyl that contains 5-8 carbon atom, N-(alkoxycarbonyloxy) aminomethyl that contains 3-9 carbon atom, 1-(N-(carbalkoxy) amino) ethyl that contains 4-10 carbon atom, 3-benzo [c] furanonyl, 4-crotonolactonyl, gamma-butyrolactone-4-base, two-N, N-(C 1-C 2) alkylamino (C 2-C 3) alkyl (for example (beta-dimethyl-aminoethyl), carbamyl-(C 1-C 2) alkyl, N, N-two (C 1-C 2) alkyl-carbamoyl-(C 1-C 2) alkyl and piperidino-(1-position only), pyrrolidyl-or morpholino (C 2-C 3) alkyl.
Equally, if compound of the present invention comprises alcohol functional group, prodrug can be by replacing the hydrogen atom of alcohol radical to form with following group: (C for example 1-C 6) chain alkyloyloxyethyl methyl, 1-((C 1-C 6) the chain alkyloyloxyethyl) ethyl, 1-methyl isophthalic acid-((C 1-C 6) the chain alkyloyloxyethyl) ethyl, (C 1-C 6) alkoxy carbonyl yloxy ylmethyl, N-(C 1-C 6) the carbalkoxy aminomethyl, succinyl, (C 1-C 6) alkanol, alpha-amino group (C 1-C 4) alkyloyl, aroyl and α-aminoacyl, or α-aminoacyl-α-aminoacyl, wherein each α-aminoacyl group is independently selected from naturally occurring L-amino acid, P (O) (OH) 2,-P (O) (O (C 1-C 6) alkyl) 2Or glycosyl (by sloughing the group that hemiacetal formula carbohydrate hydroxyl produces).
If compound of the present invention comprises amine functional group, prodrug can be by replacing the hydrogen atom of amido to form with following group: R for example X-carbonyl, R XO-carbonyl, NR xR x'-carbonyl is R wherein XAnd R X' be (C independently of one another 1-C 10) alkyl, (C 3-C 7) cycloalkyl, phenmethyl, perhaps R X-carbonyl is natural α-aminoacyl or natural α-aminoacyl-natural α-aminoacyl ,-C (OH) C (O) OY X, (Y wherein XBe H, (C 1-C 6) alkyl or phenmethyl) ,-C (OY X0) Y X1Y wherein X0Be (C 1-C 4) alkyl and Y X1Be ((C 1-C 6) alkyl, carboxyl (C 1-C 6) alkyl, amino (C 1-C 4) alkyl or N-(C 1-C 6) alkylamino alkyl or N, N-two (C 1-C 6) the alkylamino alkyl ,-C (Y X2) Y X3, Y wherein X2Be H or methyl and Y X3Be N-(C 1-C 6) alkylamino or N, N-two (C 1-C 6) alkylamino, morpholino, piperidines-1-base or tetramethyleneimine-1-base.
Term used herein " significant quantity " meaning refers to treat the compound of an amount of the inventive method of specific disease and pathology symptom.Certainly the specific dosage of the compound of the administration according to the present invention will be comprised compound, route of administration, patient's state and the severity decision of pathological symptom that quilt is treated of for example administration by the special fact around this situation.
Advantageously, the present invention also provides the human consumer to be used for the treatment of the medicine box of disease.Medicine box comprises the pharmaceutical composition that a) comprises estrogen agonist/antagonist and pharmaceutically acceptable carrier, vehicle or thinner; And optional b) specification sheets that uses this specified disease method of medicine composite for curing is described.Specification sheets can indicate that also this medicine box is to be used for the treatment of disease, reduces the susceptibility that the side effect relevant with the oestrogenic hormon administration followed simultaneously basically.
" medicine box " that uses among the application comprises container, the bottle that for example separates or the quick-fried bag that separates that contains unit dosage separately.This container can be any shape commonly used known in the art or form, its by pharmaceutically acceptable material for example paper or cardboard case, glass or Plastic Bottle or jar, reclosable sack (tablet that for example contains " filling with again " is used for putting into different containers) or have independent dosage and make from the Blister Package that packing extrudes according to treatment plan.The container that uses can depend on the formulation accurately that relates to, and for example Chang Yong presspaper box generally is not used for containing liquid suspension.Feasible is more than one container can one be used from the individual packaging to sell single formulation.For example, tablet can be included in the bottle, itself and be included in the box.
The example of such medicine box is a so-called blister packages.Blister Package is known in packaging industry, just is being widely used in the packing of pharmaceutical unit dosage forms (tablet, capsule etc.).Blister Package generally is made up of the tetanic relatively material of a slice, the preferably laminated covering of transparent plastics of this material.In wrapping process, in plastic tab, form crypts.This crypts has the one packaged tablet or the size and dimension of capsule, perhaps can have to hold a plurality of packaged tablets and/or the size and dimension of capsule.Then, tablet or capsule correspondingly are placed in the crypts, seal the tetanic relatively material of this sheet facing to plastic tab on the face of thin slice, thin slice is relative with the direction that wherein forms crypts.As a result, according to requiring tablet or capsule by single sealing or be sealed in together in the crypts between plastic tab and the sheet.The intensity of preferred sheet is so that the crypts place forms an opening in sheet thus so that be pressed on the crypts and can take out tablet or capsule from Blister Package by adding with hand.Take out tablet or capsule by described opening then.
Perhaps, it is desirable that a kind of memory aid of writing is provided, wherein this memory aid of writing is a kind of message and/or explanation that contains for doctor, pharmacist or patient, for example to be close to the numeral of tablet or capsule, wherein should numeral corresponding to the fate that should absorb tablet or capsule scheme of regulation like this or contain the form of the card of same type information.Another example of this memory aid is the schedule that is printed on the card, and is for example following " first week, Monday, Tuesday, " ... etc.. " second week, Monday, Tuesday ... " etc.Other variations of memory aid will be easy to find out." per daily dose " can be single tablet or capsule or several tablet or the capsule that will use in given a day.
The specific embodiment of another of this medicine box is to be designed to distribute next divider of dosage one every day.Preferably, this divider is equipped with memory aid, so that further helps to defer to scheme.The example of this memory aid be show distributed every day dosage the mechanical counter of number.Another example of this memory aid is the microchip stores device with the battery supply of the signal combination of liquid crystal indicator or the prompting that can hear, for example reads the date that last per daily dose takes and/or reminds and when use next dose.
Based on the reading of this specification sheets and claim, will be conspicuous for those of ordinary skills for some changes of composition described here and method.Here additional claim comprises these changes.
Here all reference quoted and patent are introduced as reference.
Embodiment
Here use following abbreviation.
HOAc acetate
The Ph phenyl
The BuLi n-Butyl Lithium
Et 2The O diethyl ether
The NBSN-bromo-succinimide
The DMF dimethyl formamide
The AIBN Diisopropyl azodicarboxylate
The Me methyl
EtOH ethanol
The rt room temperature
The THN naphthane
Embodiment 1: the estrogen receptor combination.
Oestrogenic hormon and PPTN metabolite bonded avidity are measured by following method:
The cDNA clone of people's ERa:Use Expand TMHigh Fidelity PCR System is according to the specification sheets of manufacturers (Boehringer-Mannheim, Indianapolis, IN) coding region of the ERa that clones people from people's breast cancer cell mRNA by RT-PCR.The PCR product is cloned in the pCR2.1 TA clone medicine box (Invitrogen, Carlsbad, CA) sequence then.Each acceptor coding region expressed among the vehicle pcDNA3 by time cloning to Mammals (Invitrogen, Carlsbad, CA).
Mammalian cell expression.Receptor protein by overexpression in the 293T cell.(ATCC, Manassas, these cells VA) have been designed to express regularly big T antigen, therefore can duplicate the paramount number that duplicates of the plastid that contains the SV40 copy source derived from the HEK293 cell.(MD) described, use fat transfection amine 293T cell is by hER α-pcDNA3 or hER-pcDNA3 transfection for Gibco/BRL, Bethesda as manufacturers.After transfection 48 hours, cell was collected in the phosphate buffered saline (PBS) (PBS) that contains 0.5mMEDTA.Cell granulations with the PBS/EDTA washing once.All cell lysates is by using Dounce homogenizer at TEG buffer reagent (50mM Tris pH7.4,1.5mM EDTA, 50mM NaCl, 10% glycerine, 5mM DTT, 5 μ g/ml Trypsin inhibitor,Trasylols, 10 μ g/ml leupeptins, 0.1mg/ml homogenizing prepares among the PefablocTM (Pentapharm AG AG, Basel, Switzerland)).With 100,000xg Centrifugical extraction liquid 2 hours is collected supernatant liquor under 4 ℃.Total protein concentration uses BioRad reagent, and (BioRad, Hercules CA) measure.
Competition is in conjunction with test.The inhibition of PPTN metabolite [ 3H]-competition of the charcoal of estradiol bonded ability by using dextran-coatings in conjunction with test according to method measurement (the Leake RE that has described, HabibF 1987 steroid hormone receptors:assay and characterization.In:B.Green and R.E.Leake (eds) .Steroid Hormones a Practical Approach.IRL Press Ltd, Oxford.67-92.).The 293T cell extract of expressing hERa or HERP is at the PPTN metabolite that increases concentration and [3H]-estradiol (141uCi/mmol of fixed concentration, New England Nuclear, Boston, MA) exist down, in final volume is the 50mM TrisHCI pH7.4,1.5mM EDTA, 50mMNaCl, 10% glycerine, 5mM DTT, 0.5mg/mL-lactoglobulin of 0.2mL, cultivate.All PPTN metabolites are dissolved in methyl-sulphoxide or the water-containing solvent.The final concn of acceptor is 50pM, contains 0.5nM[ 3H]-estradiol.At 4 ℃ after following 16 hours, add the charcoal (20 μ L) of dextran-coating.After at room temperature 15 minutes, remove charcoal, be present in radioactive part in the supernatant liquor by the scintillation counting measurement by centrifugation.Except as otherwise noted, all reagent all from Sigma buy (St.Louis, MO).
Embodiment 2: vitro inhibition people's breast tumor cell growth.
Use the external anti-proliferative effect of two kinds of people's breast cancer cell line test PPTN metabolite: first kind, the MCF-7 cell that contains ER and PgR (PgR), second kind, there is not the MDA-MB-231 cell of ER and PgR, allow to measure and effect that ER mechanism is irrelevant.The PPTN metabolite was measured by using different estrogen agonist/antagonist concentration culturing cells for the effect of the growth of these different clones in 6 days.Measure anti-proliferative effect by direct cell count then.
The biosynthesizing of embodiment 3:PPTN metabolite in mouse.
14The dosage of C-PPTN is prepared as that concentration is the suspension of about 0.898mg/g in 0.5% methylcellulose gum (W/W).Before and after batching, measure ingredients solution in duplicate.The metabolite of PPTN is measured by the high performance liquid chromatography (HPLC) with radioactivity prospecting, and determines by the liquid chromatography (LC/MS/MS) with mass spectrum/mass spectroscopy.
For this embodiment, one group of CD-1 mouse (N=9/ sex, 25-30 gram) is used the oral gavage administration, and be placed on Nalgene metabolic cage (Nalge NuncInternational respectively with the group of 3 animals/cage (3/ sex), Rochester is used for collecting respectively urine and ight soil in NY).The pipe of the gavage of weighing before and after administration gives the actual dose of each animal with mensuration.In the sample receiver of the flushing thing of after administration, from each cage, collecting urine, ight soil and cage in 0-24,24-48,48-72,72-96,96-120,120-144 and 144-168 hour quantitatively before weigh, totally 7 days.Be recorded in the weight that urine, ight soil and cage that different time points obtains clean thing.The urine and the sample of ight soil are separated and are stored in-20 ℃ the dark up to analysis.(N=6/ sex, 25-30g) administration are used to identify the cyclic metabolism thing to second treated animal by oral gavage.In this second group, 3 animals of each sex killed after administration in 1 and 4 hour, and blood is collected in the test tube of heparinization.
Every group urine (from about 3ml in 0-48 hour pond) is centrifugal and supernatant liquor transferred in the clean test tube, under nitrogen, concentrate with vaporizer.Resistates is dissolved in about 1ml HPLC moving phase, need not to be further purified aliquots containig (80-100 μ l) is injected on the HPLC.The homogenate of the ight soil of 0-72 hour animal after the comfortable administration in the future (～2g) the each weight of collecting at interval of basis converges, and the sample that converges dilutes with acetonitrile (6ml).Suspension on magnetic stirring apparatus, stir spend the night centrifugal then.Remove supernatant liquor, use methyl alcohol (6ml) and methyl alcohol: water (50: 50,6ml) re-extract.Merge all supernatant liquors and with few aliquots containig counting.Organic solvent uses the turbine type evaporator evaporation.Resistates is dissolved in about 1ml methyl alcohol: in the ammonium acetate (1: 1).(20-50 μ l) is injected on the HPLC with aliquots containig.The blood plasma that converges (2ml, 1 and 4 hour) is used the 4ml dilution in acetonitrile, removes the albumen that is settled out by centrifugation.Particle washs with extra 2ml acetonitrile, merges both supernatant liquors.Supernatant liquor is concentrated on vaporizer, and resistates is at the methyl alcohol of 500 μ l: form again in the ammonium acetate (1: 1).(100 μ l) is injected on the HPLC with aliquots containig.
Use be equipped with air monitor (β-RAM, IN/US Systems, Inc., Tampa, (Hewlett Packard, Palo Alto California) carry out HPLC for Hewlett Packard HP1100 four-stage pump FL) and self-actuated sampler.Beckman UltrasphereT C-18 post (4.6mm * 250mm, 5um) (Beckman Coulter, Inc., F μ llerton, CA) binary mixture of going up with 10mM ammonium acetate (solvent orange 2 A) and methyl alcohol (solvent B) carries out stratographic analysis.Moving phase is made up of solvent orange 2 A/solvent B (80: 20) at first, is adjusted to solvent orange 2 A/solvent B (20: 80) linearly with 30 minutes then, was adjusted to solvent orange 2 A/solvent B (5: 95) and kept 5 minutes after 5 minutes.Made the moving phase composition turn back to initial solvent mixture with 5 minutes.Before injection next time, make about 15 minutes of this this system balance.1.0ml/min flow velocity be used for all analyses.
Use the HPLC that air monitor is arranged to divide the radioactivity in the single peak of opening to carry out the quantification of metabolite by measuring.Air monitor provides with the comprehensive printout of count per minute (CPM) and the per-cent of radiolabeled material, and the peak performance.Air monitor is operated in the mode of homogeneous liquid scintillation counting, adds in the effluent of the compatible flicker cocktail of 3ml/min and moving phase to the ultraviolet detection.
(Thermo Quest, San Jose carry out on CA) Finnigan TSQ 7000 LC/MS/MS that are identified in of metabolite.Separation joins about 50 μ l/min in the mass spectrum atmospheric ionization sources through the auxiliary electronics sputter of gas overcharging interface from the effluent of HPLC post.Remaining effluent directly enters in the flow-through cell of air monitor.By real time record, this system provides the detection of radioactivity and mass-spectrometric data to the radioactive detector response value simultaneously by the mass-spectrometric data system.About 0.2 minute of the delay that responds between two testers, wherein mass spectrometric response record are early.Approximately is operating under the 4000V at electronics sputter interface, and mass spectrum is operated in positive mode.Use argon gas under the collision air pressure of about collision energy of 30 to about 40eV and about 2.3mTorr, to carry out decomposition (CID) research of collision-induced.
Embodiment 4: the biosynthesizing of philtrum PPTN metabolite.
The about 1.93mCi/mMol's of preparation specific activity 14C-PPTN (tartrate).
Select the age to participate in research the male patient of the normal health between 18-45 year.About 12 hours patients enter in the clinical labororatory before administration, are resting on there at least 576 hours under the medical observation continuously after administration.All patients are using the normal 14C-PPTN of about 20mg free alkali (～80pCi/ patient) fasting before at least 12 hours.In the morning with open mode dosage.The meals of standard were provided after 4 hours.Preparation is suspended in the water by the PPTN with labelled with radioisotope and prepares.First requires the patient to forbid lying down, eating or drinks the beverage that contains caffeine and carbonic acid during four hours after the rug administration.
After administration, collected the blood that is enough to generate 20ml blood plasma at 24 and 48 hours in order to identify metabolite.The mark all samples is freezing immediately then.
After administration, will mix with 40 milliliters of acetonitriles from each patient's plasma sample (20ml) in 24 and 48 hours, vortex and sonication (sonicated).This mixture is centrifugal, remove supernatant liquor.This particle mixes with the 5ml acetonitrile, centrifugal, merge two supernatant liquors.Under nitrogen, supernatant concentration is extremely done.Resistates reconstitutes in 300 μ l methanol (1: 1), centrifugal to remove insoluble substance, then 100 μ l aliquots containigs are injected on the HPLC post.The PPTN metabolite that from plasma sample, extracts by having radioactivity prospecting HPLC and as determine at the LC/MS/MS described in the foregoing description 3.
Embodiment 5: the separation and the identification of mouse PPTN metabolite.
In mouse, carry out the biosynthesizing of PPTN metabolite by the method described in the embodiment 3.With the dosage of 20mg/kg to the mouse administration.From one group of mouse, collect urine and ight soil.To second group of mouse administration and collect separation and the evaluation that blood is used for the cyclic metabolism thing.Result of study is in Fig. 1-18.Fig. 1-3 is respectively the representational radiochromatogram of urine, ight soil and cyclic metabolism thing.Provided representational mass-spectrometric data determining among Fig. 4-18 together with structure by the isolating metabolite of HPLC.
Route 1
Figure C0180779300331
Embodiment 1
1-{2-[4-(6,7-dimethoxy-3,4-dihydro-naphthalene-1-yl)-phenoxy group]-ethyl }-tetramethyleneimine
At N 2250 milliliters of diethyl ether solutions that will contain 6.75 gram (0.025 mole) 1-(2-(4-bromo phenoxy group) ethyl) tetramethyleneimine down are cooled to-78 ℃.Add several milliliters of THF to keep clear solution.Drip 16.7 milliliters of 1.6M n-Butyl Lithiums, keep temperature to be lower than-70 ℃.After-78 ℃ are stirred 1 hour down, in 1 hour time, dripped and contain 5 gram (0.024 moles) 6,25 milliliters of THF solution of 7-dimethoxy-1-Tetralone an intermediate of Sertraline keep temperature to be lower than-70 ℃.After-78 ℃ are stirred 2.5 hours down, reaction is stopped by adding 100 milliliters of 2NHCI.Make reaction mixture be warming up to room temperature, regulate pH to 7 by adding 5N NaOH.Separate Et 2The O layer, water layer extracts 2 times with EtOAc.The Et that merges 2O/EtOAc layer Na 2SO 4Drying is evaporated then and is obtained 9 gram crude products, and it is purified on 400 gram silica gel, uses 95/5 CH 2Cl 2/ MeOH wash-out is used 85/15 CH then to remove initial Tetralone an intermediate of Sertraline 2The CI2/MeOH wash-out obtains 3.3 gram products.
NMR(CDCl 3)ppm：(1.97，bs，4H)，(2.55，m，2H)，(2.84，t，2H)，(2.98，bs，4H)，(3.19，s，2H)，(3.68，s，3H)，(3.84，s，3H)，(4.31，s，2H)，(5.93，t，1H)，(6.59，s，1H)，(6.73，s，1H)，(6.90，d，2H)，(7.25，d，2H)。
Mass spectrum: (parent+1): 379.8.
Raw material:
6, and 7-dimethoxy-1-Tetralone an intermediate of Sertraline (Aldrich, Milwaukee, WI).
1-[2-(4-bromo phenoxy group) ethyl] and tetramethyleneimine (Aldrich, Milwaukee, WI).
Embodiment 2
1-{2-[4-(2-bromo-6,7-dimethoxy-3,4-dihydro-naphthalene-1-yl)-phenoxy group]-ethyl }-tetramethyleneimine
At N 2With { 2-[4-(6 to containing 6 grams (0.016 mole) under the room temperature, 7-dimethoxy-3,4-dihydronaphthalene-1-yl)-phenoxy group]-ethyl }-drip 20 milliliters of DMF solution that contain 2.8 gram (0.016 mole) N-bromosuccinimides in 200 milliliters of DMF solution of tetramethyleneimine.Add AIBN (100 milligrams), reactant stirred 1 hour, then dilute with water, extract with EtOAc.EtOAc layer Na 2SO 4Drying is evaporated then and is obtained 7 gram products, need not purifying and is directly used in next step.
NMR (acetone-d 6) ppm:(1.73, m, 4H), (2.55, m, 4H), (2.80, m, 4H), (3.48, s, 3H), (3.80, s, 3H), (4.15, s, 3H), (6.24, s, 1H), (6.84, s, 1H), (7.00, d, 2H), (7.13, d, 2H).
Mass spectrum: (parent+1): 458.
Embodiment 3
1-{2-[4-(6,7-dimethoxy-2-phenyl-3,4-dihydro-naphthalene-1-yl)-phenoxy group]-ethyl }-tetramethyleneimine
Under nitrogen, restrain (0.015 mole) 1-{2-[-(2-bromo-6 with 7,7-dimethoxy-3,4-dihydronaphthalene-1-yl)-phenoxy group]-ethyl-tetramethyleneimine, 5.6 gram (0.047 mole) phenylo boric acids,, 620 milligrams of (0.00054 moles) four (triphenylphosphine) closed palladium and the mixture heating up of 7.6 gram (0.072 mole) yellow soda ash in 500 milliliters of EtOH 10 hours.Evaporation EtOH.Add entry and EtOAc, separate the EtOAc layer, use Na 2SO 4Drying is evaporated then and is obtained 9 gram oily crude products.Should on 600 gram silica gel, purify by oil, use CH 2Cl 2/ MeOH 9/1 wash-out obtains 3.6 gram products.
NMR (acetone d 6) ppm:(1.74, m, 4H), (2.60, bs, 2H), (2.71, m, 2H), (2.85, m, 6H), (3.48, s, 3H), (3.82, s, 3H), (4.10, t, 2H), (6.35, s, 1H), (6.80-7.16, m, 10H).
Mass spectrum: (parent+1): 456.
Embodiment 4
1-{2-[4-(6,7-dimethoxy-2-phenyl-1,2,3,4-tetrahydrochysene-naphthalene-1-yl)-phenoxy group]-ethyl }-tetramethyleneimine
At 30psi (206843 pascal) H 2Under the air pressure, under 50 ℃, will contain 3.6 gram (0.0079 mole) 1-{2-[4-(6,7-dimethoxy-phenyl-3,4-dihydronaphthalene-1-yl)-phenoxy groups]-ethyl }-tetramethyleneimine, 10 milliliters of 2N HCl, 30 milliliters of H 2O and 100 milliliters of solution that contain the EtOH of 1.9 gram palladium hydroxide/carbon shook in the Parr electromagnetic shaker 15 hours.Filter reaction mixture is to remove catalyzer, and evaporation EtOH adds 5NNaOH to regulate the pH to 8 of the aqueous solution.The aqueous solution extracts with EtOAc, and dry EtOAc layer evaporates the product that obtains 3.0 gram yellow oilies then.
NMR (acetone d 6) ppm:(1.65, m, 4H), (1.74, m, 1H), (1.90, d, 1H), (2.20, m, 1H), (2.53, bs, 4H), (2.63, t, 2H), (3.00, m, 2H), (2.53, d, 1H), (3.60, s, 3H), (3.80, s, 3H), (3.93, t, 2H), (4.20, d, 1H), (6.35, d, 2H), (6.45, s, 1H), (6.53, d, 2H), (6.68, s, 1H), (7.10, m, 3H).
Mass spectrum: (parent+1): 458.
Embodiment 5
6-phenyl-5-[4-(2-tetramethyleneimine-1-base-oxyethyl group)-phenyl]-5,6,7,8-tetrahydrochysene-naphthalene-2,3-glycol and 3-methoxyl group-7-phenyl-8-[4-(2-tetramethyleneimine-1-base-oxyethyl group)-phenyl]-5,6,7, the pure and mild 3-methoxyl group of 8-naphthane-2--6-phenyl-5-[4-(2-tetramethyleneimine-1-base-oxyethyl group)-phenyl]-5,6,7, the mixture of 8-tetrahydrochysene-naphthalene-2-alcohol
At N 2Under will contain 2 gram (0.0044 mole) 1-{2-[4-(6,7-dimethoxy-2-phenyl-1,2,3,4-tetrahydrochysene-naphthalene-1-yl)-phenoxy groups]-ethyl-solution of tetramethyleneimine, 80 milliliters of HOAc and 80 milliliter of 48% aqueous HBr is 90 ℃ of heating 2 hours down.Reaction mixture is cooled to 0 ℃ then in ice bath.The aqueous solution that adds 30%NH40H is to regulate pH to 10.The aqueous solution extracts with EtOAc, and the dry EtOAc layer that merges evaporates then and obtains 1.6 gram crude products.This material is purified on 120 gram silica gel, use CH 2Cl 2/ MeOH99/1, then 95/5, then 90/10 and last 85/15 wash-out obtain 520 milligrams of 3-methoxyl group-7-phenyl-8-[4-(2-tetramethyleneimine-1-base-oxyethyl group)-phenyl]-5,6,7, the pure and mild 3-methoxyl group of 8-naphthane-2--6-phenyl-5-[4-(2-tetramethyleneimine-1-base-oxyethyl group)-phenyl]-5,6,7, the mixture of 8-tetrahydrochysene-naphthalene-2-alcohol.
NMR (acetone d 6) ppm:(1.05, m, 1H), (1.24, d, 1H), (1.76, bs, 5H), (2.20, m, 1H), (3.00, m, 4H), (3.31, d, 1H), (3.82, s, 3H), (4.05, t, 2H), (4.18, d, 1H), (6.34, m, 3H), (6.53, d, 2H), (6.78, s, 1H), (7.85, d, 2H), (7.15, m, 3H), (8.20, bs, 1H).
Mass spectrum: (parent+1): 444.
6-phenyl-5-[4-of 180 milligrams (2-tetramethyleneimine-1-base-oxyethyl group)-phenyl then]-5,6,7,8-tetrahydrochysene-naphthalene-2,3-glycol.
NMR (acetone d 6): (1.65, m, 4H), (2.20, m, 1H), (2.50, m, 4H), (2.80, m, 4H), (2.95, m, 1H), (3.50, d, 1H), (3.95, t, 2H), (4.05, d, 1H), (6.33, m, 2H), (6.60, d, 2H), (6.66, s, 1H), (6.84, d, 2H), (7.10, m, 3H), (7.55, s, 2H).
Mass spectrum: (parent+1): 430
Fusing point (mp)-132-134 ℃.
Route 2
Embodiment 6
7-hydroxyl-6-methoxyl group-1-Tetralone an intermediate of Sertraline
To contain 10 gram (0.048 moles) 6,100 milliliters of HOAc of 7-dimethoxy-1-Tetralone an intermediate of Sertraline and the solution of 100 milliliter of 48% aqueous HBr heated 7 hours down at 95 ℃.Reaction mixture is cooled to room temperature, pours in the water to extract with EtOAc then.Dry EtOAc layer evaporates then and obtains 12 gram crude products.On 1200 gram silica gel, purify, use 10%Et 2The CH of O 2Cl 2Eluant solution obtains 7.5 gram products.Fusing point 147-148 ℃ (148-152 ℃ of literature value fusing point, Journal of Organic Chemistry, the 33,1968,508th page).
NMR(CDCl 3)ppm：(2.09，m，2H)，(2.58，m，2H)，(2.85，m，2H)，(3.90，s，3H)，(5.50，bs，1H)，(6.64，s，1H)，(7.55，s，1H)。
Mass spectrum: (parent+1): 193
Raw material: 6,7-dimethoxy-1-Tetralone an intermediate of Sertraline (Aldrich, Milwaukee, WI).
Embodiment 7
7-benzyloxy-6-methoxyl group-3,4-dihydro-2H-naphthalene-1-ketone
With 4.5 gram (0.0233 mole) 7-hydroxyl-6-methoxyl group-1-Tetralone an intermediate of Sertraline, 5.4 gram (0.032 mole) bromotoluenes and 10 gram (0.072 mole) K 2CO 3Mixture heating up in 150 milliliters of acetone refluxes and spends the night.Reaction mixture is poured in the water and is extracted with EtOAc then.Use Na 2SO 4Dry EtOAc layer evaporates then and obtains 7 gram crude products.Use Et 2The O crystallization obtains 4.13 gram products, is white solid, fusing point 110-111 ℃.
NMR(CDCl 3)ppm：(2.09，m，2H)，(2.55，t，2H)，(2.87，t，2H)，(3.90，s，3H)，(5.14，s，2H)，(6.65，s，1H)，(7.25-7.45，m，5H)，(7.58，s，1H)。
Mass spectrum: (parent+1): 283
Embodiment 8
1-{2-[4-(7-benzyloxy-6-methoxyl group-3,4-dihydro-naphthalene-1-yl)-phenoxy group]-ethyl }-tetramethyleneimine
Use is similar to the method for embodiment 1, by 5.13 gram (0.0182 mole) 7-benzyloxy-6-methoxyl groups-3, the hexane solution of 4-dihydro-2H-naphthalene-1-ketone, 13.63 milliliters of 1.6M n-Butyl Lithiums and 5.16 gram (0.019 mole) 1-(2-(4-bromo phenoxy group) ethyl) tetramethyleneimine obtain 3.5 gram title product.
NMR(CDCl 3)ppm：(2.05，bs，4H)，(2.30，m，2H)，(2.74，t，2H)，(3.10-3.40，m，6H)，(3.90，s，3H)，(4.45，bs，2H)，(4.95，s，2H)，(5.90，t，1H)，(6.58，s，1H)，(6.74，s，1H)，(6.80，d，2H)，(7.10，d，2H)，(7.25，m，5H)。
Mass spectrum: (parent+1): 456.
Embodiment 9
1-{2-[4-(7-benzyloxy-2-bromo-6-methoxyl group-3,4-dihydro-naphthalene-1-yl)-phenoxy group]-ethyl }-tetramethyleneimine
Use is similar to the method for embodiment 2, by 2.47 gram (0.0054 mole) 1-{2-[4-(7-benzyloxy-6-methoxyl group-3,4-dihydro-naphthalene-1-yl)-phenoxy groups]-ethyl }-tetramethyleneimine, 965 milligrams of (0.0054 mole) NBS and 90 milligrams of AIBN obtain 2.37 and restrain title product in 50 milliliters of DMF.
NMR(CDCl 3)ppm：(1.90，bs，4H)，(2.69，s，4H)，(2.88，bs，4H)，(3.10，t，2H)，(3.83，t，2H)，(4.83，s，2H)，(6.20，s，1H)，(6.65，s，1H)，(6.90，d，2H)，(7.00，d，2H)，(7.21，m，5H)
Mass spectrum: (parent+1): 536.
Embodiment 10
1-{2-[4-(7-benzyloxy-6-methoxyl group-2-phenyl-3,4-dihydro-naphthalene-1-yl)-phenoxy group]-ethyl }-tetramethyleneimine
Use is similar to the method for embodiment 3, by 2.37 gram (0.0044 mole) 1-{2-[4-(7-benzyloxy-2-bromo-6-methoxyl group-3,4-dihydro-naphthalene-1-yl)-phenoxy groups]-ethyl }-tetramethyleneimine, 1.35 restrains (0.011 mole) phenylo boric acids, 153 milligrams of (0.13 mmoles) four (triphenylphosphine) close palladium and 1.88 gram (0.017 mole) Na 2CO 3In 50 milliliters of EtOH, obtain 1.38 gram gram title product.
NMR(CDCl3)ppm：(1.83，bs，4H)，(2.70，m，6H)，(2.86，m，2H)，(2.96，m，2H)，(3.90，s，3H)，(4.14，t，2H)，(6.37，s，1H)，(6.65-7.30，m，15H)。
Mass spectrum: (parent+1): 532.
Embodiment 11
3-methoxyl group-7-phenyl-5-[4-(2-tetramethyleneimine-1-base-oxyethyl group)-phenyl]-5,6,7,8-tetrahydrochysene-naphthalene-2-alcohol
H at 30psi 2To contain 1.38 gram 1-{2-[4-(7-benzyloxy-6-methoxyl group-2-phenyl-3,4-dihydronaphthalene-1-yl)-phenoxy groups under the air pressure, under 50 ℃]-ethyl }-tetramethyleneimine, 1.46 gram palladium hydroxide/carbon, 4 milliliters of 2N HCl, 15 milliliters of H 2The mixture of O and 100 milliliters of EtOH shook in the Parr electromagnetic shaker 36 hours.Filter reaction mixture evaporates EtOH then to remove catalyzer.Add 1N NaOH to regulate ph to 8, with EtOAc extraction water solution.Dry EtOAc layer evaporates then and obtains 640 milligrams of title product.
NMR(CDCl 3)ppm：(1.80，d，1H)，(1.95，bs，4H)，(2.10，m，1H)，(2.85-3.20，m，7H)，(3.30，d，1H)，(3.88，s，3H)，(4.14，t，2H)，(6.30，d，2H)，(6.43，s，1H)，(6.50，d，2H)，(6.68，s，1H)，(6.80，m，2H)，(7.18，m，3H)
Mass spectrum: (parent+1): 444
2-OMe, 1-OH metabolite and 3-OH, 2-OMe metabolite can use in route 4 and 5 generalized method synthetic.
3-methoxyl group-6-phenyl tetrahydrochysene-naphthalene-2-alcohol metabolite can use in the route 5 generalized method synthetic.
Route 3
Figure C0180779300391
Embodiment 12
1-{2-[4-(5,6-dimethoxy-3,4-dihydro-naphthalene-1-yl)-phenoxy group]-ethyl }-tetramethyleneimine
Use is similar to the method for embodiment 1, and by 10 gram (0.048 moles) 5, the hexane solution of 6-dimethoxy-1-Tetralone an intermediate of Sertraline, 33.4 milliliters of 1.6M n-Butyl Lithiums and 13.5 gram 1-(2-(4-bromo phenoxy group) ethyl) tetramethyleneimine obtain 6.5 gram title product.
NMR(CDCl 3)ppm：(1.90，bs，4H)，(2.31，m，2H)，(2.87，t，2H)，(2.90，bs，4H)，(3.10，bs，2H)，(3.78，s，3H)，(3.82，s，3H)，(4.28，bs，2H)，(5.90，s，1H)，(6.63，d，1H)，(6.70，d，1H)，(6.90，d，2H)，(7.22，d，2H)
Mass spectrum: (parent+1): 379.8
Raw material
5,6-dimethoxy-1-Tetralone an intermediate of Sertraline, reference: Organic Process Research ﹠amp; Development, 1999,3,71-72.
Embodiment 13
1-{2-[4-(2-bromo-5,6-dimethoxy-3,4-dihydro-naphthalene-1-yl)-phenoxy group]-ethyl }-tetramethyleneimine
Use is similar to the method for embodiment 2, by 5.33 gram (0.14 mole) 1-{2-[4-(5,6-dimethoxy-3,4-dihydro-naphthalene-1-yl)-phenoxy group]-ethyl }-tetramethyleneimine, 2.5 restrains (0.014 mole) NBS and 230 milligrams of AIBN obtain 6.25 gram title product in 50 milliliters of DMF.
NMR(CDCl 3)ppm：(1.96，bs，4H)，(2.90，m，6H)，(3.05，t，2H)，(3.15，t，2H)，(3.80，s，6H)，(4.30，t，2H)，(6.35，d，1H)，(6.53，d，1H)，(6.95，d，2H)，(7.10，d，2H)
Mass spectrum: (parent+1): 458
Embodiment 14
1-{2-[4-(5,6-dimethoxy-2-phenyl-3,4-dihydronaphthalene-1-yl)-phenoxy group]-ethyl }-tetramethyleneimine
Use is similar to the method for embodiment 3, by 6.25 gram (0.0136 mole) 1-{2-[4-(2-bromo-5,6-dimethoxy-3,4-dihydro-naphthalene-1-yl)-phenoxy group]-ethyl }-tetramethyleneimine, 4.16 restrains (0.034 mole) phenylo boric acids, 472 milligrams of (0.41 mmoles) four (triphenylphosphine) close palladium and 5.78 gram (0.054 mole) Na 2CO 3In 200 milliliters of EtOH, obtain 6.3 gram title product.
NMR(CDCl 3)ppm：(1.80，bs，4H)，(2.65，bs，4H)，(2.73，t，2H)，(2.90，t，2H)，(3.00，t，2H)，(3.83，s，6H)，(4.08，t，2H)，(6.53，d，1H)，(6.60，d，1H)，(6.74，d，2H)，(6.95，d，2H)，(7.05，m，5H)。
Mass spectrum: (parent+1): 456.
Embodiment 15
1-{2-[4-(5,6-dimethoxy-2-phenyl-1,2,3,4-tetrahydrochysene-naphthalene-1-yl)-phenoxy group]-ethyl }-tetramethyleneimine
Use is similar to the method for embodiment 4, by 6.3 gram (0.0138 mole) 1-{2-[4-(5,6-dimethoxy-2-phenyl-3,4-dihydro-naphthalene-1-yl)-phenoxy group]-ethyl }-tetramethyleneimine, 7.7 gram (0.055 mole) palladium hydroxide/carbon, 5 milliliters of 2NHCI and 10 milliliters of H 2O obtains 5.06 gram title product in 100 milliliters of EtOH.
NMR (acetone d 6) ppm:(1.95, bs, 4H), (2.70, m, 1H), (2.85, bs, 4H), (2.95, m, 1H), (3.20, bs, 2H), (3.38, bs, 2H), (3.78, s, 3H), (3.82, s, 3H), (4.40, bs, 2H), (6.43, d, 1H), (6.74, d, 1H), (6.85-7.15, m, 7H)
Mass spectrum: (parent+1): 458
Embodiment 16
6-phenyl-5-[4-(2-tetramethyleneimine-1-base-oxyethyl group)-phenyl]-5,6,7,8-tetrahydrochysene-naphthalene-1,2-glycol and 2-methoxyl group-6-phenyl-5-[4-(2-tetramethyleneimine-1-base-oxyethyl group)-phenyl]-5,6,7, the pure and mild 1-methoxyl group of 8-naphthane-1--6-phenyl-5-[4-(2-tetramethyleneimine-1-base-oxyethyl group)-phenyl]-5,6,7, the mixture of 8-tetrahydrochysene-naphthalene-2-alcohol
Use is similar to the method for embodiment 5, by 2.3 gram (0.005 mole) 1-{2-[4-(5,6-dimethoxy-2-phenyl-1,2,3,4-tetrahydrochysene-naphthalene-1-yl)-phenoxy group]-ethyl }-the HBr aqueous solution of tetramethyleneimine, 80 milliliters of HOAc and 80 milliliter 48% obtains 650 milligrams of 2-methoxyl group-6-phenyl-5-[4-(2-tetramethyleneimine-1-base-oxyethyl group)-phenyl]-5,6,7, the pure and mild 1-methoxyl group of 8-naphthane-1--6-phenyl-5-[4-(2-tetramethyleneimine-1-base-oxyethyl group)-phenyl]-5,6,7, the mixture of 8-tetrahydrochysene-naphthalene-2-alcohol.
NMR(CDCl 3)ppm：(1.88，bs，6H)，(2.10，m，1H)，(2.84，bs，4H)，(3.00，bs，2H)，(3.25，dt，1H)，(3.35，d，2H)，(3.85，s，3H)，(4.10，bs，2H)，(4.25，d，1H)，(6.25-6.88，m，8H)，(7.15，m，3H)
Mass spectrum: (parent+1): 444
And 6-phenyl-5-[4-of 140 milligrams (2-tetramethyleneimine-1-base-oxyethyl group)-phenyl]-5,6,7,8-naphthane-1,2-glycol
Mass spectrum: (parent+1): 430
Route 4
Figure C0180779300421
Embodiment 17
5-hydroxyl-6-methoxyl group-1-Tetralone an intermediate of Sertraline
Use is similar to the method for embodiment 6, and by 10 gram (0.048 moles) 5, the HBr aqueous solution of 6-dimethoxy-1-Tetralone an intermediate of Sertraline, 100 milliliters of HOAc and 100 milliliter 48% obtains 7 gram title product, 163 ℃ of fusing points.
NMR(CDCl 3)ppm：(2.09，m，2H)，(2.67，t，2H)，(2.90，t，2H)，(3.92，S，3H)，(5.70，bs，1H)，(6.80，d，1H)，(7.68，d，1H)。
Mass spectrum: (parent+1): 193
Raw material
5,6-dimethoxy-1-Tetralone an intermediate of Sertraline, reference: Organic Process Research and Development,1999,3,71-72.
Embodiment 18
5-benzyloxy-6-methoxyl group-3,4-dihydro-2H-naphthalene-1-ketone
Use is similar to the method for embodiment 7, by 4.5 gram (0.024 mole) 5-hydroxyl-6-methoxyl group-1-Tetralone an intermediate of Sertraline, 5.4 gram (0.031 mole) bromotoluenes and 10 gram (0.072 mole) K 2CO 3In 100 milliliters of acetone, obtain title product (5.13 gram), by obtaining white solid with the ether crystallization, 90 ℃ of fusing points.
NMR(CDCl 3)ppm：(2.10，m，2H)，(2.55，t，2H)，(2.88，t，2H)，(3.88，s，3H)，(5.11，s，2H)，(6.63，s，1H)，(7.20-7.45，m，5H)，(7.60，s，1H)
Mass spectrum: (parent+1): 283.
Embodiment 19
1-{2-[4-(5-benzyloxy-6-methoxyl group-3,4-dihydro-naphthalene-1-yl)-phenoxy group]-ethyl }-tetramethyleneimine
Use is similar to the method for embodiment 1, by 10 gram (0.3555 mole) 5-benzyloxy-6-methoxyl groups-3, the hexane solution of 4-dihydro-2H-naphthalene-1-ketone, 9.88 gram (0.366 mole) 1-(2-(4-bromo phenoxy group) ethyl) tetramethyleneimine and 13.63 milliliters of 1.6M n-Butyl Lithiums obtains 4.3 gram title product.
NMR(CDCl 3)ppm：(1.90，bs，4H)，(2.20，m，2H)，(2.78，t，2H)，(2.90，bs，2H)，(3.10，bs，1H)，(3.84，s，3H)，(4.26，t，2H)，(4.98，s，2H)，(5.86，t，1H)，(6.65，d，1H)，(6.74，d，H)，(6.88，d，2H)，(7.25，d，2H)，(7.28-7.50，m，5H)
Embodiment 20
1-{2-[4-(5-benzyloxy-2-bromo-6-methoxyl group-3,4-dihydro-naphthalene-1-yl)-phenoxy group]-ethyl }-tetramethyleneimine
Use is similar to the method for embodiment 2, by 4.3 gram (0.0094 mole) 1-{2-[4-(5-benzyloxy-6-methoxyl group-3,4-dihydro-naphthalene-1-yl)-phenoxy groups]-ethyl }-tetramethyleneimine, 1.68 restrains (0.0094 mole) NBS and 156 milligrams of AIBN obtain 4 gram title product in 50 milliliters of DMF.
NMR(CDCl 3)ppm：(1.95，bs，4H)，(2.75，t，2H)，(2.90，t，2H)，(3.00，bs，4H)，(3.10，bs，2H)，(3.80，s，3H)，(4.33，s，2H)，(6.35，d，1H)，(6.57，d，1H)，(6.93，d，2H)，(7.15-7.30，m，5H)
Mass spectrum: (parent+1): 536
Embodiment 21
1-{2-[4-(5-benzyloxy-6-methoxyl group-2-phenyl-3,4-dihydro-naphthalene-1-yl)-phenoxy group]-ethyl }-tetramethyleneimine
Use is similar to the method for embodiment 3, by 4.0 gram (0.0075 mole) 1-{2-[4-(5-benzyloxy-2-bromo-6-methoxyl group-3,4-dihydro-naphthalene-1-yl)-phenoxy groups]-ethyl }-tetramethyleneimine, 2.28 restrains (0.186 mole) phenylo boric acids, 259 milligrams of (0.224 mmoles) four (triphenylphosphine) close palladium, 3.7 gram (0.03 mole) Na 2CO 3In 150 milliliters of EtOH, obtain 3.2 gram title product.
NMR(CDCl 3)ppm：(1.84，bs，4H)，2.83，m，2H)，(2.74，m，4H)，(2.95，m，4H)，(3.84，s，3H)，(4.10，t，2H)，(5.03，s，2H)，(6.55，d，1H)，(6.65，d，1H)，(6.75，d，2H)，(6.90-7.50，m，12H)。
Mass spectrum: (parent+1): 532
Embodiment 22
2-methoxyl group-6-phenyl-5-[4-(2-tetramethyleneimine-1-base-oxyethyl group)-phenyl]-5,6,7,8-tetrahydrochysene-naphthalene-1-alcohol
Use is similar to the method for embodiment 11, by 3.2 gram (0.007 mole) 1-{2-[4-(5-benzyloxy-6-methoxyl group-2-phenyl-3,4-dihydronaphthalene-1-yl)-phenoxy groups]-ethyl) tetramethyleneimine, 3.4 gram palladium hydroxide/carbon, 10 milliliters of 2NHCI, 30 milliliters of H 2O and 100 milliliters of EtOH obtain 2.2 gram products.
Mass spectrum: (parent+1): 444
1-methoxyl group-6-phenyl-tetrahydrochysene-naphthalene-2-alcohol metabolite can synthesize as shown in route 6.
Route 5
Figure C0180779300451
Route 6
Figure C0180779300461

Claims (5)

1. compound is selected from:
And steric isomer, tautomer, zone and configuration isomer; With and pharmacy acceptable salt.
2. the purposes of the compound of general formula (I) in the medicine of the following disease of preparation treatment, described disease is selected from: osteoporosis, mammary cancer, hyperlipidaemia, atherosclerosis, Alzheimer, cataract, sexual anesthesia, man's sexual dysfunction, colorectal carcinoma, wrinkle of skin, autoimmune disease, alopecia, acne, cardiovascular diseases, cataract, diabetes, endometriosis, woman's sexual dysfunction, hyperglycemia, fat, obsessive-compulsive disorder, premenstrual tension syndrome, prostate cancer, benign prostatomegaly, pulmonary hypertension, reperfusion injury, rheumatoid arthritis, osteoarthritis, seborrheic dermatitis, old gynecomastia, testosterone lacks, Turner's syndrome, the fibrosis in uterus, atrophic vaginitis, incontinence, uterus carcinoma, hirsutism, Bulimia nerovsa, apocleisis, hypoactive sexual desire, the property illness of swash waking up, dyspareunia, vulvismus, prolapsus, urinary tract infection, apoplexy, myocardial infarction, acute or chronic renal failure, the arterial occlusive disease of periphery, Raynaud's phenomenon, ovary, the cancer of liver and pancreas and stiff fibre cancer, neurospongioma and kidney cell cancer, promote wound healing, increase the orgasm frequency, reduce the pH of vagina;
R wherein 1Be selected from
Figure C018077930003C2
-NH(CH 2) 3COR 6；
R 5Be selected from H or CH 3
R 2, R 3, R 4And R 7Identical or different, be selected from H and OR 5And
R 6Be selected from-OH or-NHCH 2COOH,
Condition is,
(a) if R 1Be
Figure C018077930003C3
Or-NH (CH 2) 3COOH, and
(b) R 2Be OH or OCH 3, and R 3And R 7Be H, if perhaps R 1Such as in above-mentioned (a) definition, and
(c) R 2And R 7Be H, R 3Be OH or OCH 3,
R so 4Not H;
Or its optically-active, solid, zone or configuration isomer or geometrical isomer or tautomer, or its pharmacy acceptable salt.
3. the purposes of following compound in the medicine of the following disease of preparation treatment, wherein said disease is selected from: osteoporosis, mammary cancer, hyperlipidaemia, atherosclerosis, Alzheimer, cataract, sexual anesthesia, man's sexual dysfunction, colorectal carcinoma, wrinkle of skin, autoimmune disease, alopecia, acne, cardiovascular diseases, cataract, diabetes, endometriosis, woman's sexual dysfunction, hyperglycemia, fat, obsessive-compulsive disorder, premenstrual tension syndrome, prostate cancer, benign prostatomegaly, pulmonary hypertension, reperfusion injury, rheumatoid arthritis, osteoarthritis, seborrheic dermatitis, old gynecomastia, testosterone lacks, Turner's syndrome, the fibrosis in uterus, atrophic vaginitis, incontinence, uterus carcinoma, hirsutism, Bulimia nerovsa, apocleisis, hypoactive sexual desire, the property illness of swash waking up, dyspareunia, vulvismus, prolapsus, urinary tract infection, apoplexy, myocardial infarction, acute or chronic renal failure, the arterial occlusive disease of periphery, Raynaud's phenomenon, ovary, the cancer of liver and pancreas and stiff fibre cancer, neurospongioma and kidney cell cancer, promote wound healing, increase the orgasm frequency, reduce the pH of vagina;
Described compound is selected from:
And steric isomer, tautomer, zone and configuration isomer; With and pharmacy acceptable salt.
4. pharmaceutical composition, contain the compound corresponding to general formula I:
R wherein 1Be selected from
Or
-NH(CH 2) 3COR 6；
R 5Be selected from H or CH 3
R 2, R 3, R 4And R 7Identical or different, be selected from H and OR 5And
R 6Be selected from-OH or-NHCH 2COOH,
Condition is,
(a) if R 1Be
Or-NH (CH 2) 3COOH, and
(b) R 2Be OH or OCH 3, and R 3And R 7Be H, if perhaps R 1Such as in above-mentioned (a) definition, and
(c) R 2And R 7Be H, R 3Be OH or OCH 3,
R so 4Not H;
Or its optically-active, solid, position or configuration isomer or geometrical isomer or tautomer, its pharmacy acceptable salt, and pharmaceutically acceptable carrier, excipient or thinner.
5. pharmaceutical composition, the compound that wherein comprises is selected from:
Figure C018077930009C1
And steric isomer, tautomer, zone and configuration isomer; With and pharmacy acceptable salt.
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